Conventional

ANTIEPILEPTIC
DRUGS
By: Mr. Kameshwor Yadav

Mr. ysphaneendra.m

Moderator: Miss Swapna

 PROTOCOL
 INTRODUCTION
 Definition of seizure, epilepsy, convulsion

 Causes, pathophysiology of epilepsy & diagnosis

 Types of epilepsy

CLASSIFICATION OF ANTIEPILEPTIC DRUGS

PHARMACOKINETICS & DYNAMICS

THERAPY OF EPILEPSY & SEIZURE

 EPILEPSY IN WOMEN

 CONCLUSION

REFERENCES
 1/4/19 Department Of Pharmacology, KMC, Manipal 2
 INTRODUCTION
 Epilepsy is the 3rd most common neurologic disorder

 Affects approximately 3% of individuals

 About 10% of the population will have at least one seizure

 Highest incidence in early childhood & late adulthood

1/4/19 Department Of Pharmacology, KMC, Manipal 3

 DEFINITIONS
o SEIZURE
 limited periods of abnormal discharge of cerebral
neurons

o EPILEPSY (To Seize Upon / Taking Hold Of)

 Recurrent seizures due to a chronic underlying process

o CONVULSION
 Paroxysms of involuntary muscular contractions
& relaxations
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 Causes of Seizures
 Epileptogenic factors
 Precipitating factors (provocative factor)

 Sleep deprivation
Systemic disease
Metabolic derangements
Acute infection
 Drugs

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 Pathophysiology

 In normal circumstances, recurrent & collateral inhibitory

circuits in cerebral cortex limit synchronous discharge of
adjacent group of neurons

The inhibitory transmission GABA has important role in this

Evidence : drugs that block GABA receptor provokes seizures
 Conversely, excessive stimulation by excitatory
neurotransmitter such as Ach, glutamate & aspartate,
provoke seizure
Thus, it is likely that both reduction of inhibition and
excessive excitation plays part
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 Diagnosis

• Laboratory studies

• Electrophysiological studies MRI

• Brain imaging

CT Scan

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 International League against Epilepsy (ILAE) Commission
on Classification and Terminology, 2005-2009
CLASSIFICATION OF SEIZURES

FOCAL SEIZURES GENERALISED SEIZURES MAY BE

FOCAL,
GENERALISED,
OR UNCLEAR

Without dyscognitive With dyscognitive Evolution of focal

features features to generalized
seizures
1/4/19 Department Of Pharmacology, KMC, Manipal 8
 Generalized seizures

Absence Tonic clonic Tonic Clonic Atonic Myoclonic

Typical Atypical

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Some other type of epilepsy :

• Epilepsy syndrome

• Juvenile myoclonic epilepsy

• Lennox-Gastaut syndrome

• Mesial temporal lobe epilepsy syndrome

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Classification of anti epileptic drugs

1/4/19 Department Of Pharmacology, KMC, Manipal 11

 Classification of drugs
 Barbiturates & deoxybarbiturate

 Phenobarbitone

 Primidone
intermediate

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 Hydantoin

 Phenytoin

 Fosphenytoin

 Iminostilbene

 Carbamazepine

1/4/19Oxcarbamazepine
Department Of Pharmacology, KMC, Manipal 13
  Succinimide
 Ethosuximide

 Aliphatic carboxylic acid

 Valproic acid

 Divalproex

1/4/19 Department Of Pharmacology, KMC, Manipal 14

  Benzodiazepines
 Clonazepam
 Diazepam
 Lorazepam
 Clobazam

 Phenyltriazine
 Lamotrigine

 Cyclic GABA analogues

 Gabapentin
1/4/19
Department
Pregabalin
Of Pharmacology, KMC, Manipal 15
 General pharmacokinetics of antiepileptic drugs
 Absorption is usually good, 80% to 100%

 Phenytoin, valproic acid highly bound to plasma proteins

but not other conventional drugs

 All must enter the CNS

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 Most conventional drugs (except gabapentin)
metabolized in liver & in some cases active
metabolite formed

 Many antiseizure drugs are medium to long acting

because slow plasma clearance

 Older antiseizure drugs are potent inducer of hepatic

microsomal enzyme ex. carbamazepine & phenytoin

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 Drugs that inhibit antiseizure drug metabolism or displace
anticonvulsants from plasma protein

 Drugs that induce hepatic drug metabolizing enzyme make

antiseizure drugs inadequate for seizure control

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 Pharmacokinetics &
adverse effect of
individual drugs

1/4/19 Department Of Pharmacology, KMC, Manipal 19

Drugs Pharmacokinetics Interactions & ADR

Phenobar  Slow oral absorption  Sedative action

bitone  80-120 hr. plasma half life
 Steady state reached after 2-3 weeks
 Long term- behavioral
abnormalities, diminution of
intelligence, impairment learning &
memory, hyperactivity in children &
mental confusion in older people
 Rashes, megaloblastic anaemia &
osteomalacia

Primidone  2/3 metabolized to phenobarbitone &  Anaemia, leukopenia

phenyl ethylmalonate
 Half life 6-14 hr

phenytoin  Slow oral absorption Therapeutic levels-

 Bioavailability different according to  Gum hypertrophy
manufacturer  Hirsutism
 80-90 % plasma protein binding  Foetal hydantoin syndrome
 Metabolism is capacity limited  Inhibit insulin release-
hyperglycaemia

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Drugs Pharmacokinetics Interactions & ADR

High plasma level-

 Cerebellar & vestibular manifestations
 Drawsiness, behavioral alterations
 Epigastric pain & nausea, vomiting
 I .V. cause local injury
 I .V. cause Fall in B.P. & arrhythmia & ECG monitoring
Interactions
 With Phenobarbitone
 With carbamazepine
 With valproate
 Enzyme inhibitor-chloramphenicol, isoniazid, cimetidine
 Competitively Inhibits warfarin metabolism
 Phenytoin induce microsomal enzyme
 Acidic drugs displace it from protein binding sites
 Sucralfate binds phenytoin in GIT

Fosphenyt-  Water soluble

oin  Mixed in saline
& glucose
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Drugs Pharmacokinetics Interactions & ADR

Carbamazepine  Oral absorption is slow & variable  Sedation, dizziness, vertigo,

 75% bound to the plasma protein diplopia & ataxia
 By oxidation in liver produce 10-11  Diarrhoea, vomiting worsening
epoxy carbamazepine of seizure
 Initially half life 20-40hr then 10-20  Water retention &
hyponatremia
 Minor foetal malformation
 Enzyme inducer reduce efficacy
of haloperidol, oral
contraceptives
 Metabolism induced by
phenobarbitone, phenytoin &
vice versa
 Erythromycin, fluoxetine,
isoniazid inhibit metabolism

Oxcarbazepine  Active metabolite is glucuronide  Weak enzyme inducer

conjugate  Better tolerated
 Lower risk of hepatotoxicity
 Hyponatraemia is more

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Drugs Pharmacokinetics
Ethosuximide  Slowly but completely
absorbed
 Not protein bound
 Half life 48 hr. in adults,
32 hr. in children
Valproic acid  Good oral absorption
 90% bound to plasma
 Half life 10-15 hr.
Divalproex Slow oral absorption but
1/4/19 same bioavailability
Department Of Pharmacology, KMC, Manipal
Interactions & ADR
 Gastrointestinal intolerance
 Anorexia, vomiting, loose motions, heart
burn
 Asymptomatic rise in serum transaminase
 Fulminant hepatitis & pancretitis
 Spinal bifida & neural tube defect
 Increases phenobarbitone & lamotrigine by
inhibiting metabolim
 Displace phenytoin
 Inhibit hydrolysis of epoxide metabolite of
carbamazepine
 With carbamazepine foetal abnormality is
more
Gastric tolerance better
23
Drugs Pharmacokinetics Interactions &
ADR

Clonazepam  Good oral absorption  Sedation &

 Completely metabolized in liver dullness
 Half life 24 hr.

Clobazam  Good oral absorption

 Half life 18hr & metabolite has >35hr

Diazepam  Half life 30-60 hr.

 Rectal & iv route

Lamotrigine  Good oral absorption  Ataxia,

 Completely metabolized in liver diplopia,
 Half life is 24 hr. but reduced to 16hr. dizziness

Gaba analogues  Lipophilic GABA derivative

 Well absorbed orally
 Excreted unchanged
 Half life 6hr.

1/4/19 Department Of Pharmacology, KMC, Manipal 24

MECHANISMS OF ACTION
1. ProlongationNaof channel inactivation
+

h
Phenytoin
Carbamazepine
Valproate
Lamotrigine
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2. Inhibition of T type
Ca ++

channel
Ca++

Ethosuximide
Valproate
lamotrigine
1/4/19 Department Of Pharmacology, KMC, Manipal 26
 3. Facilitation of GABA mediated chloride channel opening

Gaba
Gabp.
GABA-T
SSA

Valpr.
Barbiturate Benzodiazepine

Barbiturates

Benzodiazepine

 Valproic acid cl

Gabapentin
1/4/19 Department Of Pharmacology, KMC, Manipal 27
 THERAPY OF SEIZURES & EPILEPSY
1. Treatment of underlying conditions

Sole cause of seizure is metabolic disturbance

If the apparent cause of seizure is medicine

Seizure caused by structural CNS lesion

2. Avoidance of precipitating factors

Situations that lower seizure threshold

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3. Antiepileptic drug therapy

Recurrent seizure

 When to initiate

Single seizure

 Selection of drugs

Older drugs Newer drug

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Generalised-Onset Tonic- Focal Typical Atypical
Clonic Absence Absence,
Myoclonic,
Atonic
First line
Lamotrigine Lamotrigine Valproic acid Valproic acid
Valproic acid Carbamazepine Ethosuximide Lamotrigine
Oxcarbazepine Lamotrigine
Phenytoin

Alternative
Phenytoin Valproic acid Lamotrigine Clonazepam
Carbamazepine Gabapentin Clonazepam Clobazam
Oxcarbamazepine Phenobarbital
Phenobarbital Primidone
Primidone

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 Initiation & monitoring of drugs

 GOAL-prevents seizures & side effects of treatment

 Starting doses are usually the lowest value

 Subsequent increases should be made only after

achieving a steady state with the previous dose

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 Monitoring of serum antiepileptic drug levels can be
very useful for establishing the initial dosing schedule

 Concentration of free drug that reflects extracellular

levels in the brain and correlates best with efficacy
(impaired liver & renal disease)

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If seizures continue, despite gradual increases to the
maximum
tolerated dose

It become necessary to switch another antiepileptic drugs

usually done by maintaining the patient on the first drug while

a second drug is added

second drug should be adjusted to decrease seizure frequency

without causing toxicity

Once this is achieved the first drug can be gradually withdrawn

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 When & how to discontinue
• Approximately one-third of patients with epilepsy do not
respond to treatment with a single antiepileptic drug

• In most cases, the initial combination therapy combines

first line drugs (i.e. carbamazepine, oxcarbazepine,
lamotrigine, valproic acid, levetiracetam and phenytoin)

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• These drugs are unsuccessful then the addition of
other drugs such as topiramate, zonisamide,
lacosamide, or tiagabine is indicated

• If there is no improvement, a third drug can be

added while the first two are maintained

1/4/19 Department Of Pharmacology, KMC, Manipal 35

 Gradually stopped to avoid increased seizure
frequency and severity

 In general, withdrawal of anti-absence drugs is easier

than withdrawal of drugs needed for focal or
generalized tonic-clonic seizures

 Barbiturates and Benzodiazepines are the most

difficult to discontinue; weeks or months may be
required, with very gradual dosage decrements,

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Treatment of refractory epilepsy

 One-third of patients with epilepsy do not respond to

treatment with a single antiepileptic drug

 In most cases, the initial combination therapy combines

first-line drugs

1/4/19 Department Of Pharmacology, KMC, Manipal 37

 Treatment of status epilepticus

 Status epilepticus refers to continuous

seizures or repetitive, discrete seizures with
impaired consciousness in the inter-ictal
period

 Traditional definition ( 15-30min)

 Practical definition

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 Status epilepticus

Generalized convulsive Non convulsive

status epilepticus (GCSE) status epileptics

 Both types are treated by same approach

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• GCSE is an emergency and must be treated
immediate ， because cardiorespiratory
dysfunction ， hyperthermia ， and metabolic
derangements can develop as a consequence of
prolonged seizures ， and these can lead to
irreversible neuronal injury

1/4/19 Department Of Pharmacology, KMC, Manipal 40

1/4/19 Department Of Pharmacology, KMC, Manipal 41
 EPILEPSY IN WOMEN
 Catamenial epilepsy

 Increase in seizure frequency around the time of

menses

 Increase in antiepileptic drug dosages

 Natural progestin or intramuscular

medroxyprogesterone

1/4/19 Department Of Pharmacology, KMC, Manipal 42

  Pregnancy
 Seizure frequency

Unchanged in ̴50% of women

30% 20%
 Fetal abnormality

Mother with epilepsy : 5-6%

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 Uncontrolled convulsive seizures on the mother and fetus
outweighs the risk of teratogenic effects of antiepileptic drugs

 Monotherapy, at the lowest effective dose

 Folate ( 1 -4 mg/d)

Antiepileptic drugs are Enzyme inducing –reversible deficiency

of vitamin K dependent factors in newborns

 Mother should be treated with oral vitamin K (20 mg/ d ，
phylloquinone) in the last 2 weeks of pregnancy, and the infant
should receive intramuscular vitamin K ( 1 mg) at birth
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• Note:-
Phenytoin has been implicated in a specific syndrome
called fetal hydantoin syndrome, although not all
investigators are convinced of its existence and a similar
syndrome has been attributed both to phenobarbital
and to carbamazepine

 Valproate, has been also implicated in a specific

malformation, spina bifida. Pregnant woman taking
valproic acid or sodium valproate has a 1–2% risk of having
a child with spina bifida

Topiramate has shown some teratogenicity in animal

1/4/19 Department Of Pharmacology, KMC, Manipal 45
testing
  Contraception

 Enzyme inducing drugs & oral contraceptives

 Alternative contraceptives

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 Breast feeding

 Ratio of drug concentration in human breast milk relative

to serum ranges from ̴5% (valproic acid) to 300%
(levetiracetam)

however, NO evidence of harm but potential benefit of

breast feeding supports to continue the breast feeding

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 To conclude….

This is an old saying, “Old is gold”, which holds true for

conventional antiepileptic drugs, and is highlighted by the
fact that older drugs are still first line drugs for the
treatment of major types of epilepsy, while only 2 newer
drugs levetiracetam (focal) and topiramate (atypical
absence, myoclonic, atonic) are being used as first line drugs
in epilepsy.

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 References
1. Tripathi KD. Essentials of medical pharmacology,7th ed.
New Delhi, London, Philadelphia, Panama : Jaypee
brothers medical publishers (p) LTD; 2013 .P.411-424

2. Katzung Bertaam G., Trevor Anthony J. Basic & clinical

pharmacology, 13th ed. New Delhi: McGraw Hill Education
(india) private limited; 2015. p.396-420

1/4/19 Department Of Pharmacology, KMC, Manipal 49

3. Kasper D.L., Fauci A. S., Hauser S.L., Longo D.L., Jameson J.L., Loscalzo J.
HARISON’STM principles of internal medicine,19th ed. New York, Chicago,
San Francisco, Athens, London, Madrid, Mexico City, Milan, New Delhi,
Singapore, Sydney, Toronto: McGraw-Hill education; 2015.P. 2542-2558

4. Lu Matthias C. Antoconvulsants. In: Beale John M., Block John H. Wilson

& Gisvold’s Textbook of organic medicinal & pharmaceutical chemistry, 12th
ed. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong kong,
Sydney, Tokyo: Lippincott Williams & Wilkins, a Wolters Kluwer business;
2011. P. 491-503

1/4/19 Department Of Pharmacology, KMC, Manipal 50

1/4/19 THANK YOU…!!
Department Of Pharmacology, KMC, Manipal 51